T-lymphocytes are known to play a central role in the pathogenesis of many inflammatory and autoimmune diseases, including rheumatoid arthritis. The activation of T-cells by antigen-presenting cells is the primary event in the initiation of the inflammatory process, which subsequently leads to the activation of other inflammatory cells and in turn the release of pro-inflammatory cytokines, chemotactic agents and matrix-degrading enzymes.
Multiple sclerosis is a chronic demyelinating inflammatory disease of the central nervous system. T-cell proliferation leads to release of the pro-inflammatory cytokines (primarily IL-2 and IFN-γ) and the recruitment of leucocytes (including macrophages) which orchestrate the inflammatory response.
In chronic obstructive pulmonary disease (COPD), activation of neutrophils and macrophages by proliferating CD8+ T-cells leads to the release of pro-inflammatory cytokines and elastin-degrading enzymes, which causes a chronic and progressive degradation of lung tissues and ultimately reduction in respiratory function.
Crohn's disease and ulcerative colitis are chronic inflammatory diseases of the intestines collectively known as inflammatory bowel disease (IBD). It is likely that both these disorders are actually heterogeneous groups of diseases that have different causes, but share similar perpetuating stimuli and common pathways of tissue injury. Once again, T-cells are central to the progression of this collection of diseases, leading to the activation of immune, mesenchymal and epithelial cells, recruitment of circulating effector cells and ultimately gastrointestinal tissue damage.
In psoriasis, the presentation of antigen by Langerhan's cells to CD4+ T-cells leads to the synthesis of cytokines which stimulate keratinocyte proliferation and the expression of adhesion molecules by endothelial cells and keratinocytes. Keratinocytes in turn are stimulated to produce their own cytokines which can act in an autocrine and/or paracrine manner to maintain the psoriatic process.
There is a similarly strong rationale for the central involvement of T-cells in many other inflammatory diseases, including systemic lupus erythematosus (SLE), asthma, lupus nephritis, glomerulonephritis, IgA nephropathy, gingivitis, periodontal disease, atopic dermatitis, scleroderma and graft vs host disease (GVHD). Thus, inhibitors of T-cell proliferation may have utility in the treatment of a range of inflammatory and autoimmune diseases.
Rhein (1,8-dihydroxyanthraquinone-3-carboxylic acid) is a well-characterised anti-inflammatory agent, with recognised utility in a range of inflammatory diseases. While this agent has not been demonstrated to inhibit T-cell proliferation, it is known to inhibit the production of pro-inflammatory cytokines (IL-1β and TNFα) in human osteoarthritic synovium and chondrocytes (J. Martel-Pelletier et al, Journal of Rheumatology, 1998, 25 (4), 753-762) and to inhibit cytokine gene expression in a model of lupus nephritis (S. Lemay et al, Kidney International, 1996, 50 (1), 85-93). In common with the tetracyclines, rhein and its pro-drug diacerein have been shown to down-regulate the production of pro-matrix metalloproteinases (pro-MMPs −1, −3, −9 and −13) while upregulating the production of tissue inhibitor of metalloproteinases −1 (TIMP-1) from rabbit articular chondrocytes (T. Tamura et al, Osteoarthritis and Cartilage, 2001, 9 (3), 257-263).
Rhein is disclosed as having utility in arthritis and multiple sclerosis (U.S. Pat. No. 4,346,103) and in diabetic nephropathy (EP0990441A1), diseases where over-production of IL-1β is particularly implicated. The widespread use of rhein has been somewhat limited by its rather poor physicochemical properties. This issue is not addressed completely with the well characterised pro-drug diacerein, where utility in the clinical setting is again limited by poor physicochemical properties (P. Nicolas et al, Clin. Pharmacokinet., 1998, 35 (5), 347-359).